A great deal of research is currently underway to develop treatments and cures for viral infections in humans and in animals. Notably the incidence of AIDS and ARC in humans is increasing at an alarming rate The five year survival rate for those with AIDS is dispiriting and AIDS patients, whose immune systems have been seriously impaired infections including Kaposi's sarcoma and Pneumocystis carninii pneumonia. No cure is known and current treatments are largely without adequate proof of efficacy and have numerous untoward side effects. Fear of the disease has resulted in social ostracism of and discrimination against those having or suspected of having the disease.
Retroviruses are a class of ribonucleic acid (RNA) viruses that replicate by using reverse transcriptase to form a strand of complementary DNA (cDNA) from which a double stranded, proviral DNA is produced. This proviral DNA is then randomly incorporated into the chromasomal DNA of the host cell making possible viral replication by later translation of the integrated DNA containing the viral genome.
Many of the known retroviruses are oncogenic or tumor causing. Indeed the first two human retroviruses discovered, denoted human T-cell leukemia virus I and II or HTLV-I and II, were found to cause rare leukemias in humans after infection of T-lymphocytes. The third such human virus to be discovered, HTLV-III, now referred to as HIV, was found to cause cell death after infection of T-lymphocytes and has been identified as the causative agent of acquired immune deficiency syndrome (AIDS) and AIDS related complex (ARC).
Retroviruses have, in addition to the usual viral capsid, an outer membrane of lipid and glycoprotein, similar to the membrane of ordinary cells. Indeed the lipid of the retroviral membrane is probably derived directly from the membrane of a previously infected host cell, however, the glycoprotein of the viral membrane is unique to the virus itself and is coded for by the viral genome. Infection of a host cell by a retrovirus initially relies on the interaction of various receptors on the host cell surface with the glycoprotein membrane envelope of the virus. Subsequently the virus and cell membranes fuse and the virion contents are released into the host cell cytoplasm. The glycoprotein envelope of the retroviruses plays an important role in both the initial interaction of the virion and the host cell and in the later fusion of the viral and host cell membranes.
Interference with the formation of the viral envelope glycoprotein could prevent the initial virus-host cell interaction or subsequent fusion or could prevent viral duplication by preventing the construction of the proper glycoprotein required for the completion of the viral membrane. It has been recently reported that the nonspecific glycosylation inhibitors 2-deoxy-D-glucose and .beta.-hydroxy-norvaline inhibit expression of HIV glycoproteins and block the formation of syncytia H. A. Blough, et al., Biochemical and Biophysical Research Communications, 141(1), 33-38 (1986). Viral multiplication of HIV-infected cells treated with these agents is stopped, presumably because of the unavailability of glycoprotein required for viral membrane formation. In another report, the glycosylation inhibitor 2-deoxy-2-fluoro-D-mannose was found to exhibit antiviral activity against influenza infected cells by preventing the glycosylation of viral membrane protein. W. McDowell, et al., Biochemistry, 24(27), 8145-52 (1985). This report also studied the antiviral activity of 2-deoxyglucose and 2-deoxy-2-fluoroglucose and found that each inhibit viral protein glycosylation by a different mechanism. Many other known glycosylation inhibitors are found to have no antiviral activity. Thus the antiviral activity against membraned viruses, in general, and the anti-retroviral activity, specifically, of glycosylation inhibitors is quite unpredictable.
Castanospermine is an alkaloid which has been isolated from the seeds of Castanospermum australe and it has the following formula: ##STR1## Systematically, this compound can be named in several ways as follows [1S-(1.alpha.,6.beta.,7.alpha.,8.beta.,8a.beta.)]-octahydro-1,6,7,8-indoli zinetetrol or (1S,6S,7R,8R,8aR)-1,6,7,8-tetrahydroxyindolizidine or 1,2,4,8-tetradeoxy-1,4,8-nitrilo-L-glycero-D-galcto-octitol. The term "castanospermine" or the first systematic name will be used in the discussion below
The isolation of this compound and the determination of its structure has been described by L. D. Hohenshutz, et al., Phytochemistry, 20, 811 (1981). As part of his study of castanospermine, Hohenshutz obtained castanospermine tetraacetate by the reaction of castanospermine with a very large excess of acetic anhydride but there is no suggestion of any other esters of castanospermine in the article
The applicants have now discovered that certain esters of castanospermine are useful in the treatment of various retroviral infections including in the treatment of AIDS and ARC resulting from infection by HIV or other retroviruses.